Uveal melanoma is the most common and malignant intraocular tumor in adults. Metastases appear in 19% to 35% of the patients within 5 years of diagnosis of uveal melanoma. The liver is the primary organ for the development of metastases, and up to 95% of the patients who die from uveal melanoma have liver metastases at the time of death. Although the treatment for primary uveal melanoma has improved substantially over the past two decades, there have been no significant advances in the management of metastases and as such, the five-year survival time for uveal melanoma patients has not changed in over 30 years. Regrettably, there still remains no effective treatment for uveal melanoma metastases. This Research Plan addresses four specific aims relating to the immunobiology of uveal melanoma and the development of liver metastases. The first aim will test the hypothesis that primary uveal melanoma expresses a chemokine receptor (i.e., CXCR4), that contributes to the organ-specific development of liver metastases. However, unlike other tumors that metastasize to the liver, such as colon cancer, uveal melanoma cells down regulate their CXCR4 expression after colonizing the liver. The second aim will test the hypothesis that two novel T cell populations, one expressing the gamma/delta T cell receptor (gamma/delta Tcells) and the other expressing natural killer (NK) markers, play important roles in controlling the development of liver metastases arising from intraocular melanomas. The third aim will test the hypothesis that uveal melanoma cells and their metastases elaborate indoleamine dioxygenase (IDO), a potent immunosuppressive molecule, which might serve as an escape mechanism for eluding T cell-mediated immune surveillance. The fourth aim will evaluate the therapeutic efficacy of a monoclonal antibody directed against human CD54 in controlling liver metastases in a nude mouse model of uveal melanoma.